In this study conducted amongst Indian male tobacco users with upper aero-digestive tract (UADT) squamous carcinoma, 30 patients with multiple primary neoplasms (MPN) were compared with 28 age and sex matched patients with a single primary neoplasm (SPN) for various environmental factors (form of tobacco use, alcohol, radiotherapy for index cancer) and genetic parameters (family history of UADT cancers and GSTT1/GSTM1 genotype). The GSTM1/T1 null genotype, seen in 60% patients with MPN versus 33% patients with SPN (P=0.03) had an odds ratio of 3.7 [CI=1.14-11.99; P=0.03] for developing MPN. Tobacco use in the form of smoking with or without chewing, as opposed to only chewing, and regular alcohol intake were the two other factors with almost three fold increased risk for the development of MPN, although, the effect was not statistically significant. All three patients with a family history of UADT cancer developed MPN, suggesting an inherited predisposition.